DESCRIPTION (adapted from the application) The insulin-producing B-cells of the pancreas constitute only about 1-2 percent of the pancreas. There is currently no way to visualize the B-cells non-invasively. If a non-invasive imaging technology were to become available, it would greatly aid studies of the natural history of the diabetes disease process, determining the stage of the disease process in pre-diabetics, evaluating the efficacy of interventional therapies and monitoring the survival of transplanted islets in diabetic individuals. My Department has a mature biological imaging program based on positron emission tomography (PET) instrumentation, chemistry and applications. In particular, my colleagues have initiated a program to monitor in living animals, the ectopic expression of reporter genes in a non-invasive, repetitive and quantitative fashion. To do this, they have developed several different PET reporter genes, viral delivery systems, labeled PET probes, and a microPET system that allows high-resolution imaging of mice. These tools have allowed repetitive in vivo monitoring of reporter gene expression in transgenic mice, and in mice treated with gene therapy vectors containing PET reporter genes. The goal of this application is to apply these recently developed technologies towards the development of animal models and B-cell imaging procedures that will be useful to the diabetes community. We propose to generate transgenic NOD mice that express PET reporter genes in their B-cells. These transgenic mice will be used to establish the parameters with which to image the B-cells in the pancreas and in islet grafts. This will serve as a feasibility study to evaluate whether human B-cells, engineered to express PET reporter genes (e.g., via viral vectors), could be monitored following their transplantation in man. If successful, future studies could evaluate the status of the B-cells, as well as monitor the migration patterns of immune cells (that carry another type of PET reporter) during the disease process in NOD mice and following immunotherapy. We will also evaluate the ability of PET to monitor and quantitate the level of expression of genes in which were introduced into the islets by gene therapy. This collaborative project will promote interactions with a cadre of established researchers with expertise in biological imaging - which is a major way of synergistically developing the next generation of technologies and diabetes researchers.